ESC. Update of the ESC Guidelines on Medical Therapy. John Camm. ICM Internationales Congress Center München

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1 ESC 2012 ICM Internationales Congress Center München Update on Consensus Statements on Management of Atrial Fibrillation European Heart Rhythm Association Update of the ESC Guidelines on Medical Therapy 2012 John Camm St. George s University of London United Kingdom

2 ESC 2012 ICM - Internationales Congress Center München Update on Consensus Statements on Management of Atrial Fibrillation European Heart Rhythm Association Update of the ESC Guidelines on Medical Therapy 2012 John Camm Conflicts of Interest: Consultant/Advisor/Speaker Advisor / Speaker : Astra Zeneca, Gilead, Merck, Menarini, Sanofi Aventis, Servier, Xention, Bayer, Boehringer Ingleheim, Bristol Myers Squibb, Daiichi, Pfizer, Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Actelion, GlaxoSmithKline, InfoBionic, Incarda, Johnson and Johnson, Mitsubishi, Novartis, Takeda

3 Management of Atrial Fibrillation Focus of 2012 Update Anticoagulation risk stratification Use of novel oral anticoagulants (NOACs) Left atrial appendage occlusion/excision Pharmacological cardioversion (vernakalant) Oral antiarrhythmic therapy (dronedarone, and short term therapy) Left atrial catheter ablation European Heart Journal doi: /eurheartj/ehs253

4 New /Modified Recommendations Topic A B C I IIa IIb III Anticoagulation risk stratification Anticoagulation Left atrial appendage occlusion Pharmacological cardioversion Oral antiarrhythmic therapy Left atrial catheter ablation Total n (%) 12 (35%) 20 (59%) 2 (9%) 12 (35%) 17 (50%) 3 (9%) 2 (9%) European Heart Journal doi: /eurheartj/ehs253

5 Anticoagulation - General Recommendations for prevention of thromboembolism in nonvalvular AF - general Recommendations Class Level Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except in those patients (both male and female) who are at low risk (aged <65 years and lone AF), or with contraindications. The choice of antithrombotic therapy should be based upon the absolute risks of stroke/thromboembolism and bleeding and the net clinical benefit for a given patient. The CHA 2 DS 2 -VASc score is recommended as a means of assessing stroke risk in non-valvular AF. I A I I A A ESC Update on the Management of AF: European Heart Journal/EP- Europace 2012

6 Proportion of patients free of thromboembolism (%) Proportion of patients free of thromboembolism (%) CHADS 2 vs CHA 2 DS 2 VASc All patients with atrial fibrillation not treated with VKAs in Denmark CHADS 2 score = 0 Heart failure Hypertension Diabetes mellitus Age 75 years fulfilled the study inclusion criteria 100 CHADS 2 score = 0 Female sex Heart failure Hypertension Vascular disease Age years Diabetes mellitus Years of follow-up Years of follow-up Kaplan-Meier estimate of probability of remaining free of thromboembolism with CHADS 2 score 0 and 1. Only patients with CHADS 2 scores 0 and 1 were included, and patients were censored at death for causes other than thromboembolism Kaplan-Meier estimate of probability of remaining free of thromboembolism with CHA 2 DS 2 score 0 and 1. Only patients with CHA 2 DS 2 scores 0 and 1 were included, and patients were censored at death for causes other than thromboembolism Olesen JB et al, BMJ 2011;342:d124

7 CHA 2 DS 2 -VASc Assessment of Thromboembolic Risk Congestive heart failure/ 1 LV dysfunction Hypertension 1 Age 75 2 Diabetes mellitus 1 Stroke/TIA/TE 2 Vascular disease 1 (CAD, AoD, PAD) Age Sex category (female) 1 Score 0 9 Validated in 1084 NVAF patients not on OAC with known TE status at 1 year in Euro Heart Survey OR for stroke if: Female: 2.53 ( ), p=0.029; Vascular disease: 2.27 ( ), p=0.063 Score Annual stroke rate, % n Lip GYH, et al. Chest 2009 Olesen JB et al. BMJ 2011;342:124

8 Recommendations Class Level In patients with a CHA 2 DS 2 -VASc score of 0 (i.e., aged <65 years with lone AF) who are at low risk, with none of the risk factors, no antithrombotic therapy is recommended. In patients with a CHA 2 DS 2 -VASc score 2, OAC therapy with: adjusted-dose VKA (INR 2 3); or a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban) d. is recommended, unless contraindicated. In patients with a CHA 2 DS 2 -VASc score of 1, OAC therapy with: adjusted-dose VKA (INR 2 3); or a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban) d. should be considered, based upon an assessment of the risk of bleeding complications and patient preferences. I I IIa B A A d = pending EMA/FDA approval prescribing information is awaited European Heart Journal doi: /eurheartj/ehs253

9 Category W vs Placebo Stroke Prevention: Anticoagulant Effect Meta-analysis of stroke or systemic embolism Relative Hazard Ratio (95% CI) W vs Dabigatran 110 W vs Rivaroxaban ICH W vs W low dose W vs Aspirin W vs Aspirin + Clop W vs Ximelagatran W vs Dabigatran 110 W vs Rivaroxaban W vs Dabigatran 150 W vs Apixaban Favours Favours other warfarin Rx W vs Dabigatran 150 W vs Apixaban 5 W vs Dabigatran 110 W vs Rivaroxaban W vs Dabigatran 150 W vs Apixaban Major bleeding Favours Favours other warfarin Rx Modified from Camm AJ. EHJ 2009;30:2554 5

10 Anticoagulation - NOACs Recommendations for prevention of thromboembolism in nonvalvular AF - NOACs Recommendations Class Level When adjusted-dose VKA (INR 2 3) cannot be used in a patient with AF where an OAC is recommended, due to difficulties in keeping within therapeutic anticoagulation, experiencing side effects of VKAs, or inability to attend or undertake INR monitoring, one of the NOACs, either: a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban) d is recommended. Where OAC is recommended, one of the NOACs, either: a direct thrombin inhibitor (dabigatran); or an oral factor Xa inhibitor (e.g., rivaroxaban, apixaban) d should be considered rather than adjusted-dose VKA (INR 2 3) for most patients with non-valvular AF, based on their net clinical benefit. ESC Update on the Management of AF: European Heart Journal/EP- Europace 2012 I IIa B A

11 Anticoagulation General Antiplatelet Agents Recommendations for prevention of thromboembolism in nonvalvular AF - general Recommendations Class Level When patients refuse the use of any OAC (whether VKAs or NOACs), antiplatelet therapy should be considered, using combination therapy with aspirin mg plus clopidogrel 75 mg daily (where there is a low risk of bleeding) or less effectively aspirin mg daily. IIa B European Heart Journal doi: /eurheartj/ehs253

12 Choice of Anticoagulant Atrial fibrillation Valvular AF* Yes Yes No (i.e. non-valvular AF) < 65 years and lone AF (including females) * Includes rheumatic valvular AF, hypertrophic cardiomyopathy, etc. ** Antiplatelet therapy with aspirin plus clopidogrel, or less effectively aspirin only, may be considered in patients who refuse any OAC No Assess risk of stroke (CHA 2 DS 2 -VASc score) 0 1** 2 Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences No antithrombotic therapy NOAC VKA European Heart Journal doi: /eurheartj/ehs253

13 Stroke / Systemic Embolism Rate (%) Dabigatran - Stroke and Systemic Embolism after Cardioversion 1983 cardioversions were performed in 1270 patients 4 2 3,5 3 p = ,5 2,5 2 p = With TEE prior to cardioversion Without TEE prior to cardioversion 1, , , D110 mg BID D150 mg BID Warfarin 0 Nagarakanti R et al. Circulation. 2011;123:

14 Anticoagulation - Cardioversion Recommendations for prevention of thromboembolism in nonvalvular AF Peri-cardioversion Recommendations Class Level For patients with AF of 48 h duration, or when the duration of AF is unknown, OAC therapy (e.g., VKA with INR 2-3 or dabigatran) is recommended for 3 weeks prior to and for 4 weeks after cardioversion, regardless of the method (electrical or oral/i.v. pharmacological). In patients with risk factors for stroke or AF recurrence, OAC therapy, whether with dose-adjusted VKA (INR 2-3) or a NOAC, should be continued lifelong irrespective of the apparent maintenance of sinus rhythm following cardioversion. I I B B ESC Update on the Management of AF: European Heart Journal/EP- Europace 2012

15 Stroke Outcome After Ablation vs AAD Therapy: Propensity-Matched Analysis Market Scan Research Database Ablation: n = 3194 AAD: n = 6028 Used in propensity-matched analysis: 801 pairs Follow-up: 27 months Stroke/TIA free survival HR = 0.60 ( ) AF, ablation AF, no ablation Log-rank p = Years 8.3% 14.1% Reynolds MR, et al. Circ Cardiovasc Qual Outcomes 2012;5 [epub ahead of press] Characteristic Age group, % > 80 Ablation n = AAD n = Men, % Hypertension, % Diabetes, % CHF, % CAD, % Stroke/TIA, % CHADS 2, % Warfarin Warfarin use decline to 50% in both groups

16 1 o efficacy endpoint 1 o safety endpoint PROTECT-AF Primary Safety and Efficacy Endpoints Major bleeding (IC, GI) Serious procedure related complications: Tamponade Device embolization Stroke Intention-to-treat analysis All strokes CV deaths Unexplained death Holmes DR, et al. Lancet 2009;374: RR = 1.69 ( ) Non-inferiority > 99.9% Superiority 90% Watchman 7.4 per 100 pt-yrs Warfarin 4.4 per 100 pt-yrs ,095 Days RR = 0.62 ( ) Non-nferiority > 99.9% Superiority 98.6% Warfarin 4.4 per 100 pt-yrs Watchman 3.0 per 100 pt-yrs Days 730 1,095

17 LAA Closure/Occlusion/Excision Recommendations for LAA closure/occlusion/excision Recommendations Class Level Interventional, percutaneous LAA closure may be considered in patients with a high stroke risk and contraindications for long-term oral anticoagulation. Surgical excision of the LAA may be considered in patients undergoing open heart surgery. IIb IIb B C European Heart Journal doi: /eurheartj/ehs253 European Heart Journal doi: /eurheartj/ehs253

18 Choice of Anti-coagulant Atrial fibrillation Valvular AF* Yes Yes No (i.e. non-valvular AF) < 65 years and lone AF (including females) * Includes rheumatic valvular AF, hypertrophic cardiomyopathy, etc. ** Antiplatelet therapy with aspirin plus clopidogrel, or less effectively aspirin only, may be considered in patients who refuse any OAC No Assess risk of stroke (CHA 2 DS 2 -VASc score) 0 1** 2 Oral anticoagulant therapy Assess bleeding risk (HAS-BLED score) Consider patient values and preferences No antithrombotic therapy NOAC VKA European Heart Journal doi: /eurheartj/ehs253

19 Intravenous Vernakalant Consistent Conversion Rates * ** ** ** CRAFT: Dosing was 2+3 mg/kg; data represents % converted at 60 min post last dose; AF duration 3-72 hours ACT I, III & IV: AF <7 days ACT II: Post CABG and valvular AF study; AF duration 3-72 hours ACT IV: A placebo group was not included in the ACT IV study ** P ** P

20 1 0 and 2 Efficacy Endpoint Results Time and Rate of Conversion from AF to SR Within 90 Minutes P < (Log-Rank test) 51.7% 10 min 25 min 35 min Vernakalant 24.1% 42.2% 45.7% Amiodarone 0.9% 2.6% 3.5% 5.2% Median Time To conversion in Vernakalant Responders was 11 minutes

21 Pharmacological Cardioversion Recommendations for pharmacological cardioversion of recent-onset AF Recommendations When pharmacological cardioversion is preferred and there is no or minimal structural heart disease, intravenous flecainide, propafenone, ibutilide, or vernakalant are recommended. In patients with AF 7 days and moderate structural heart disease (but without hypotension <100 mm Hg, NYHA class III or IV heart failure, recent [<30 days] ACS, or severe aortic stenosis) intravenous vernakalant may be considered. Vernakalant should be used with caution in patients with NYHA class I II heart failure. Class Level Intravenous vernakalant may be considered for cardioversion of postoperative AF 3 days in patients after cardiac surgery. IIb B I IIb A B European Heart Journal doi: /eurheartj/ehs253

22 yes Recent-onset AF Haemodynamic instability no electrical Patient/physician choice Cardioversion Recent Onset AF Emergency Elective pharmacological Structural heart disease Severe Moderate None Electrical cardioversion Intravenous amiodarone a Ibutilide should not be given when significant left ventricular hypertrophy ( 1.4 cm) is present. b Vernakalant should not be given in moderate or severe heart failure, aortic stenosis, acute coronary syndrome or hypotension. Caution in mild heart failure. c Pill-in-the-pocket technique preliminary assessment in a medically safe environment and then used by the patient in the ambulatory setting. Intravenous Ibutilide* vernakalant Intravenous amiodarone Intravenous flecainide propafenone vernakalant Intravenous amiodarone Pill-in-the pocket (high dose oral) flecainide propafenone European Heart Journal doi: /eurheartj/ehs253

23 Cumulative Hazard Cumulative Hazard Cumulative Hazard Cumulative Hazard Permanent versus Non-Permanent AF CV hospitalization or death % HR = 0.76 P < ATHENA Placebo 10 Dronedarone 0 Months CV hospitalization or death % 40 HR = 0.74 permanent P = Mean follow-up 21 5 months 10 Months PALLAS Stroke, MI, SEE or CV Death % HR = 2.29 P = Months CV hospitalization or death % HR = 1.95 P = Months Hohnloser SH et al. N Engl J Med. 2009;360: Connolly S et al. N Engl J Med. 2011;365:

24 Dronedarone Therapeutic Indication September 2009 MULTAQ is indicated in adult clinically stable patients with a history of, or current non-permanent atrial fibrillation (AF) to prevent recurrence of AF or to lower ventricular rate (see section 5.1). September 2011 MULTAQ is indicated for the maintenance of sinus rhythm after successful cardioversion in adult clinically stable patients with paroxysmal or persistent atrial fibrillation (AF). Due to its safety profile (see sections 4.3 and 4.4), Multaq should only be prescribed after alternative treatment options have been considered. MULTAQ should not be given to patients with left ventricular systolic dysfunction or to patients with current or previous episodes of heart failure. Multaq (Dronedarone) SmPC Europe, September 2011

25 Details of the Hepatic Failure Cases Two cases of liver failure and transplant, year-old female History: intermittent AF, high BP & stable CAD. Received Dronedarone for 4.5m, no LFTs during this period. Concomitant medications: lisinopril, hydrochlorothiazide, bisoprolol, amlodipine, l-thyroxine, simvastatin, ASA, alendronic acid, tiotropium, formoterol. Presentation: 2 weeks prior to hospitalization was exhausted and tired. 1 week prior to admission discontinued Dronedarone, and on admission had jaundice, coagulopathy, transaminitis and hyperbilirubinemia; hepatic encephalopathy after 9 days. She was transplanted Pre-transplant workup no other cause 72-year-old female History: paroxysmal AF and Sjögren s syndrome. Received Dronedarone for 6 m, with no LFTs during this period. Concomitant medications: metoprolol, amlodipine, omeprazole, warfarin, alprazolam, calcium, biotin and multivitamins. Presentation: Developed weakness, abdominal pain, coagulopathy, transaminitis and hyperbilirubinemia. She was transplanted 1 month later. Pre-transplant no other cause. A liver biopsy prior to transplant revealed 60-70% necrosis. Joghetaei N, et al. Circ Arrhythm Electrophysiol. 2011;4: U.S. FDA Drug Safety Communication.

26 Reporting rate in patient-years x 1000 Dronedarone 2 year Post-marketing Safety Data Based on the estimated 440,000 patients treated with dronedarone up to 30 June 2011* Reporting rate per 1000 patient-years for serious adverse events per periodic safety update period 1 Jul Jan Feb Jul Aug Jan Feb Jun 2011 *Estimated. IMS/MIDAS Worldwide Monthly Database, Standard Units Sold until 30 June 2011, reported Aug 2011

27 FLEC-SL: Primary outcome (ITT) Flecainide 4 weeks vs long-term therapy 635 patients, Mean age 64 years, Primary outcome: Time to persistent AF, or death Monitored by telemetric ECG Kirchhof P et al Lancet Jul 21;380(9838):

28 Oral Antiarrhythmic Drugs Recommendations for oral antiarrhythmic agents Recommendations Dronedarone is recommended in patients with recurrent AF as a moderately effective antiarrhythmic agent for the maintenance of sinus rhythm. Class Level I A Short-term (4 weeks) antiarrhythmic therapy after cardioversion may be considered in selected patients e.g., those at risk for therapy associated complications. Dronedarone is not recommended in patients with permanent AF. III B IIb B European Heart Journal doi: /eurheartj/ehs253

29 Choice of Oral Antiarrhythmic Drug Minimal or no structural heart disease Significant structural heart disease Treatment of underlying condition and prevention of remodelling ACE-I / ARB / statin HHD CHD HF No LVH LVH sotalol dronedarone / flecainide / propafenone / sotalol dronedarone dronedarone amiodarone amiodarone amiodarone European Heart Journal doi: /eurheartj/ehs253

30 Pocket Guidelines European Heart Journal doi: /eurheartj/ehs253

31 Thank you for your attention

32 Thank you for your attention